Polyunsaturated fatty acids (PUFAs) are major components of lipid compounds and complexes, such as phospholipids and lipoproteins, which provide a number of structural and functional characteristics to a wide range of biological constituents, such as the cell membranes. PUFAs are essential for the proper development, maintenance and repair of tissue. Other biological functions of PUFAs include their involvement in the expression of some genes and their role as precursor molecules for conversion into biologically active metabolites that regulate critical physiological functions. Consequently, a lack of, or imbalance in, PUFA levels has been attributed to certain pathological conditions.
FIGS. 1, 2 and 3 show the required desaturation and elongation steps for the production of long chain fatty acids in the n-3, n-6 and n-9/n-7 PUFA families, respectively. Fatty acid chain elongation systems have been found in liver, brain, kidney, lung, adrenals, retina, testis, small intestine and blood cells, namely leukocytes (Cinti et al., 1992, Prog. Lipid Res., 31: 1-51).
Elongase genes have been identified in Arabidopsis (James et al., 1995, Plant Cell, 7: 309-319 and in C. elegans (WO 00/55330, September, 2000, Napier J. A.). Three separate elongase genes, ELO1, ELO2 and ELO3, have been identified from S. cerevisiae. ELO1 elongates myristic acid to palmitic acid (Toke D. A. and Martin C. E., 1996, J. Biol. Chem., 271: 18413-18422) while ELO2 and ELO3 elongate long chain saturated fatty acids (Oh et al., 1997, J. Biol. Chem., 272: 17376-17384).
Deficiencies in polyunsaturated fatty acids (PUFAS) have been associated with a number of diseases such as eczema, cardiovascular disorders, inflammation, psychiatric disorders, cancer, cystic fibrosis, pre-menstrual syndrome and diabetes (Horrobin D. F. [ed.], 1990, Omega-6 Essential Fatty Acids: Pathophysiology and Roles in Clinical Medicine, Wiley-Liss, NY and Mazza G. and Domah B. D. [eds.], 2000, Herbs, Botanicals and Teas, Technomic Publishers, Lancaster, Pa.). Diets supplemented with PUFAs have been attempted as a treatment for a number of these conditions. The level of success for such applications has varied considerably.
Low levels of linoleic acid (18:2n-6, LA), dihomogamma-linolenic acid (20:3n-6, DGLA) and arachidonic acid (20:4n-6, AA) in adipose tissue of males have been correlated with increased mortality from coronary heart disease (Riemersma et al., 1986, Br. Med. J. [Clin. Res. Ed.], 292: 1423-1427). The supplementation of LA and alpha-linolenic acid (18:3n-3, ALA) to patients suffering from hypertension did not increase the tissue levels of AA or eicosapentaenoic acid (20:5n-3, EPA) which indicates defective desaturation and elongation in the n-6 and n-3 fatty acid systems (Singer et al., 1984, Prostaglandins Leukot. Med., 15: 159-165). Misoprostol, a prostaglandin E1 (PGE1) analogue, has been successfully used to treat peripheral vascular disease (Goszcz et al., 1998, Methods Find. Exp. Clin. Pharmacol., 20: 439-445). PGE1 is a cyclooxygenase product of DGLA.
It has been observed that PUFAs can alleviate and correct some of the symptoms of diabetic neuropathy (Dines et al., 1993, Diabetologia, 36: 1132-1138 and Cotter et al., 1995, Diabetic Neuropathy: New Concepts and Insights, Elsevier Science B. V., Amsterdam, pp. 115-120). Researchers have speculated that the production or modulation of the cyclooxygenase and lipoxygenase metabolites of the n-3 and n-6 fatty acid families is responsible for some of these beneficial effects.
Most of the lipid metabolism disorders are characterized by a deficiency in essential fatty acids. This deficiency has been attributed to altered rate-limiting steps of delta-6-desaturation (D6D) and/or delta-5-desaturation (D5D) in PUFA biosynthesis.